Method of Treating Pain Caused by Inflammation

ABSTRACT

A method of treating or inhibiting, in particular, pain caused by inflammation in a mammal by administering to the mammal an effective inflammatory pain alleviating amoung of a (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound or a physiologally acceptable salt thereof, such as the hydrochloride or citrate salt.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending application Ser. No.11/133,190, filed May 20, 2005, now U.S. Pat. No. ______, which in turnis a continuation of International Patent Application No.PCT/EP2003/012882, filed Nov. 18, 2003, designating the United States ofAmerica, and published in German as WO 2004/047823, the entiredisclosure of which is incorporated herein by reference. Priority isclaimed based on German Patent Application Nos. 102 54 785.8, filed Nov.22, 2002, and 103 26 103.6, filed Jun. 6, 2003.

FIELD OF THE INVENTION

The present invention relates to a method of treating or inhibitingpain, particularly pain caused by inflammation or inflammatory pain.

BACKGROUND OF THE INVENTION

The treatment of chronic and non-chronic pain conditions is extremelyimportant in medicine. There is currently a worldwide demand foradditional, not exclusively opioid-based, but highly effective, paintreatment. The urgent need for action for patient-oriented andpurposeful treatment of chronic and non-chronic pain conditions, thisbeing taken to mean the successful and satisfactory treatment of painfor the patient, is documented in the large number of scientific paperswhich have recently appeared in the field of applied analgesics andfundamental research work on nociception.

Even if the analgesics that are conventionally used for treating pain,for example opioids, NA- and 5HT-reuptake inhibitors, NSAIDS and alsoCOX inhibitors, are analgesically effective, side effects neverthelesssometimes occur, in particular in the case of the more active opioids.

SUMMARY OF THE INVENTION

The object of the present invention is therefore to provide new methodsfor treating, in particular, inflammatory pain or pain due toinflammation.

It has been found that(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol or aphysiologically acceptable salt thereof is unexpectedly particularlyeffective in treating or inhibiting inflammatory pain.

Accordingly, the invention relates to a method of treating or inhibitinginflammatory pain in a mammal in need thereof, comprising administeringto said mammal a pharmacologically effective amount of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol or aphysiologically acceptable salt thereof. Particularly preferredphysiologically acceptable salts are the hydrochloride salt and thecitrate salt. The active substance may also be administered in the formof a solvate, particularly a hydrate.

The active substance is advantageously administered in the form of asubstantially pure stereoisomer, in particular, enantiomer ordiastereomer, or in the form of a mixture of the stereoisomerscontaining predominantly the 1R,2R enantiomers or diastereomers.

The active substance 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolcorresponds to a compound of the following formula I:

in which

X is H;

R¹ is ethyl;R² is methyl;

R³ is H;

R⁹, R¹¹ and R¹³ are each H; andone of R¹⁰ and R¹² is OH, while the other is H.

The active substance is advantageously administered in the form of asubstantially pure stereoisomer, in particular, enantiomer ordiastereomer, or in the form of a mixture of the stereoisomerscontaining predominantly the 1R,2R enantiomers or diastereomers.

In the context of this invention, alkyl and cycloalkyl radicals aretaken to mean saturated and unsaturated (but not aromatic), branched,unbranched and cyclic hydrocarbons which may be unsubstituted or singlyor multiply substituted. In this case C₁₋₂ alkyl represents C1 or C2alkyl, C₁₋₃ alkyl represents C1, C2 or C3 alkyl, C₁₋₄ alkyl representsC1, C2, C3 or C4 alkyl, C₁₋₅ alkyl represents C1, C2, C3, C4 or C5alkyl, C₁₋₆ alkyl represents C1, C2, C3, C4, C5 or C6 alkyl, C₁₋₇ alkylrepresents C1, C2, C3, C4, C5, C6 or C7 alkyl, C₁₋₈ alkyl represents C1,C2, C3, C4, C5, C6, C7 or C8 alkyl, C₁₋₁₀ alkyl represents C1, C2, C3,C4, C5, C6, C7, C8, C9 or C10 alkyl and C₁₋₁₈ alkyl represents C1, C2,C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 orC18 alkyl. Furthermore C₃₋₄ cycloalkyl represents C3 or C4 cycloalkyl,C₃₋₅ cycloalkyl represents C3, C4 or C5 cycloalkyl, C₃₋₆ cycloalkylrepresents C3, C4, C5 or C6 cycloalkyl, C₃₋₇ cycloalkyl represents C3,C4, C5, C6 or C7 cycloalkyl, C₃₋₈ cycloalkyl represents C3, C4, C5, C6,C7 or C8 cycloalkyl, C₄₋₅ cycloalkyl represents C4 or C5 cycloalkyl,C₄₋₆ cycloalkyl represents C4, C5 or C6 cycloalkyl, C₄₋₇ cycloalkylrepresents C4, C5, C6 or C7 cycloalkyl, C₅₋₆ cycloalkyl represents C5 orC6 cycloalkyl and C₅₋₇ cycloalkyl represents C5, C6 or C7 cycloalkyl.With respect to cycloalkyl, the term also comprises saturatedcycloalkyls, in which one or two carbon atoms are replaced by aheteroatom, S, N or O. However, the term cycloalkyl also includes singlyor multiply, preferably singly, unsaturated cycloalkyls without aheteroatom in the ring, if the cycloalkyl is not an aromatic system. Thealkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl(ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, cyclopropyl, 2-methylyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl,cyclooctyl, but also adamantyl, CHF₂, CF₃ or CH₂OH and pyrazolinone,oxopyrazolinone, [1,4]dioxan or dioxolan.

In this case, in conjunction with alkyl and cycloalkyl—unless this isnot explicitly defined otherwise—the term substituted in the context ofthis invention denotes the substitution of at least one (optionally alsomore) hydrogen radical(s) for F, Cl, Br, I, NH₂, SH, OCH₃, SCH₃,N(CH₃)₂, NHCH₃ or OH, wherein “multiply substituted” or “substituted”with multiple substitution denotes that the substitution is made both ondifferent and on the same atoms multiply with the same or differentsubstituents, for example threefold on the same carbon atom as in thecase of CF₃ or at different points as in the case of—CH(OH)—CH=CH—CHCl₂. Particularly preferred substituents in this caseare F, Cl and OH. With respect to cycloalkyl, the hydrogen radical canalso be replaced by OC₁₋₃ alkyl or C₁₋₃ alkyl (singly or multiplysubstituted or unsubstituted respectively), in particular methyl, ethyl,n-propyl, i-propyl, CF₃, methoxy or ethoxy.

The term (CH₂)₃₋₆ is taken to mean —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂— and CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, (CH₂)₁₋₄ to mean—CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—, (CH₂)₄₋₅ to mean—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—, etc.

An aryl radical denotes ring systems with at least one aromatic ring butwithout heteroatoms even in only one of the rings. Examples are phenyl,naphthyl, fluoroanthenyl, fluorenyl, tetralinyl or indanyl, which can beunsubstituted or singly or multiply substituted.

A heteroaryl radical denotes heterocyclic ring systems with at least oneunsaturated ring, which contain one or more heteroatoms from the groupcomprising nitrogen, oxygen and/or sulphur and which can also be singlyor multiply substituted. Examples of suitable heteroaryl groups includefuran, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine,benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole,benzodioxolan, benzodioxan, carbazole, indole and quinazoline.

In this case, in conjunction with aryl and heteroaryl, substituteddenotes the substitution of the aryl or heteroaryl by R²², OR²², ahalogen, preferably F and/or Cl, a CF₃, a CN, a NO₂, a NR²³R²⁴, a C₁₋₆alkyl (saturated), a C₁₋₆ alkoxy, a C₃₋₈ cycloalkoxy, a C₃₋₈ cycloalkylor a C₂₋₆ alkylene. In this case the radical R²² represents H, a C₁₋₁₀alkyl, preferably a C₁₋₆ alkyl, an aryl or heteroaryl radical or an arylor heteroaryl radical bound by C₁₋₃ alkyl, saturated or unsaturated, ora C₁₋₃ alkylene-group-bound aryl or heteroaryl radical, wherein thesearyl or heteroaryl radicals must not themselves be substituted by arylor heteroaryl radicals. The radicals R²³ and R²⁴, which may be the sameor different, represent H, a C₁₋₁₀ alkyl, preferably a C₁₋₆ alkyl, anaryl radical, a heteroaryl radical or an aryl or heteroaryl radicalbound by saturated or unsaturated C₁₋₃ alkyl or a C₁₋₃alkylene-group-bound aryl or heteroaryl radical, wherein these aryl orheteroaryl radicals must not themselves be substituted by aryl orheteroaryl radicals. Alternatively, the radicals R²³ and R²⁴ togethermean CH₂CH₂OCH₂CH₂, CH₂CH₂NR²⁵CH₂CH₂ or (CH₂)₃₋₆. The radical R²⁵represents H, a C₁₋₁₀ alkyl, preferably a C₁₋₆ alkyl, an aryl radical, aheteroaryl radical or an aryl or heteroaryl radical bound by saturatedor unsaturated C₁₋₃ alkyl or a C₁₋₃ alkylene-group-bound aryl orheteroaryl radical, wherein these aryl or heteroaryl radicals must notthemselves be substituted by aryl or heteroaryl radicals.

The term “salt” denotes any form of the active ingredient according tothe invention in which it assumes or is charged with an ionic form andis coupled to a counter ion (a cation or anion) or is in solution. Thisalso includes complexes of the active ingredient with other moleculesand ions, in particular complexes which are complexed by ioninteraction. In particular this is taken to mean (and this is also apreferred embodiment of this invention) physiologically acceptablesalts, in particular physiologically acceptable salts with cations orbases and physiologically acceptable salts with anions or acids or evena salt formed with a physiologically acceptable acid or physiologicallyacceptable cation.

The “term physiologically acceptable salt with anions or acids” denotes,in the context of this invention, salts of at least one of the compoundsaccording to the invention—usually protonated, for example onnitrogen—as a cation with at least one anion which are physiologicallyacceptable—in particular when administered to humans and/or mammals. Inthe context of this invention this denotes, in particular, the saltformed with a physiologically acceptable acid, namely salts of therespective active ingredient with inorganic or organic acids, which arephysiologically acceptable—in particular when administered to humansand/or mammals. Examples of physiologically acceptable salts of specificacids are salts of: hydrochloric acid, hydrobromic acid, sulphuric acid,methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1b6-benzo[d]isothiazol-3-one (saccharic acid),monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid,nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoicacid, α-lipoic acid, acetyl glycine, acetylsalicylic acid, hippuric acidand/or aspartic acid. Hydrochloride salt and citrate are particularlypreferred.

The term “salt formed with a physiologically acceptable acid”, in thecontext of this invention, is taken to mean salts of the respectiveactive ingredient with inorganic or organic acids which arephysiologically acceptable—in particular when administered to humansand/or mammals. Hydrochloride and citrate are particularly preferred.Examples of physiologically acceptable acids include: hydrochloric acid,hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid,acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid,fumaric acid, lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1λ⁶-benzo[d]isothiazol-3-one (saccharic acid),monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid,nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoicacid, α-lipoic acid, acetyl glycine, acetylsalicylic acid, hippuric acidand/or aspartic acid.

The term “physiologically acceptable salt with cations or bases”denotes, in the context of this invention, salts of at least one of thecompounds according to the invention—usually a (deprotonated) acid—as ananion with at least one, preferably inorganic, cation, which arephysiologically acceptable, in particular when administered to humansand/or mammals. The salts of the alkali and alkaline-earth metals areparticularly preferred, but also NH₄ ⁺, in particular however (mono) or(di) sodium, (mono) or (di) potassium, magnesium or calcium salts.

The term “salt formed with a physiologically acceptable cation” is takento mean, in the context of this invention, salts of at least one of therespective compounds as an anion with at least one inorganic cation,which are physiologically acceptable, in particular when administered tohumans and/or mammals. The salts of the alkali and alkaline-earth metalsare particularly preferred, but also NH₄ ⁺, in particular however (mono)or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.

Substituted 1-phenyl-3-dialkylamino-propane compounds and the productionthereof are known from U.S. Pat. No. 6,248,737 (=DE 44 26 245).

The term “COX-II inhibitors” refers to selective inhibitors of COX II,the inducible isoform of cyclooxygenase. Cyclooxygenase is a synonym forprostaglandin endoperoxide synthase; an enzyme that combines thefunction of a dioxgenase and a peroxidase and, as a key enzyme,catalyses the conversion of arachidonic acid into prostaglandin H2 orperoxides (see Walter de Gruyter, Pschyrembel, 258^(th) edition; RocheLexikon Medizin, 4^(th) edition). Further information regarding COX-IIinhibitors, in particular listings thereof, may be found on pp. 13 to126 and in particular 21 to 31 of “Analgesics, From Chemistry andPharmacology to Clinical Application”; Buschmann et al (eds.), 1^(st)edition, Wiley-VCH, 2002. All of the content of this chapter is part ofthe description of this invention. The term “COX-II inhibitors” refersin particular, by way of example, to Celecoxib, Rofecoxib, Etoricoxib,Valdecoxib, Parecoxib, Etodolac, Meloxicam or Nimesulide. Celecoxib,which is sold under the name LOSEC® or Prilosec® or CELEBREX®, andRofecoxib, which is sold under the name VIOXX®, are of particularimportance. The term “selectively correspondingly preferred” denotesthat the compound displays more pronounced inhibition of COX II than ofCOX I and/or in particular exhibits an IC₅₀ that is ≧5 lower on COX IIthan on COX 1.

In particular, the 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolcompound of the invention in which R³ =H is in the form of the 1R,2Rdiastereomer having the relative configuration Ia

In particular in mixtures which have a relatively high content of thisdiastereomer in comparison to the other diastereomer are used, or asubstantially pure diastereomer is used. In particular the compound(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol is used,preferably as the hydrochloride or as the citrate.

In one preferred embodiment, the3-(3-dimethylamino-1-ethyl-2-methyl-proply)-phenol compound according tothe invention may be used in combination with a COX-II inhibitor.Particularly preferred COX-II inhibitors may be selected from the groupconsisting of Celecoxib, Rofecoxib, Etoricoxib, Valdecoxib, Parecoxib,Etodolac, Meloxicam and Nimesulide, especially particularly preferablyCelecoxib or Rofecoxib.

The active ingredients according to the invention are toxicologicallysafe, so the invention also relates to a pharmaceutical compositioncontaining an active ingredient combination according to the invention;and optionally suitable additives and/or auxiliaries or activeingredients;

Suitable additives and/or auxiliaries, in the context of this invention,are any substances known to a person skilled in the art from the priorart for obtaining galenical formulations. The choice of theseauxiliaries and the amounts thereof to be used depend on whether thepharmaceutical preparation is to be administered orally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,buccally, rectally or topically. Preparations in the form of tablets,chewing tablets, dragees, capsules, granules, drops, juices or syrupsare suitable for oral administration, solutions, suspensions, easilyreconstitutable dry preparations and sprays are suitable for parenteral,topical and inhalative administration. Suppositories for rectaladministration are a further possibility. Administration in a deposit,in dissolved form, in a carrier foil or a plaster, optionally with theaddition of agents to promote skin penetration, are examples of suitablepercutaneous administration preparations. Examples of auxiliaries andadditives for oral administration preparations include blasting agents,lubricants, binders, fillers, mould release agents, optionally solvents,flavouring agents, sugar, in particular carrier agents, diluents, dyes,antioxidants, etc. Waxes and fatty acid esters may, inter alia, be usedas suppositories and carrier substances, preservatives and suspensionauxiliaries, etc. may be used as parenteral administration agents. Theamount of active ingredient to be administered to the patient varies asa function of the weight of the patient, the method of administrationand the severity of the illness. The compounds according to theinvention may be released after a delay from preparations that may beadministered orally, rectally or percutaneously. In the indicationaccording to the invention, suitable retarding formulations, in the formof a “once-daily” preparation that only has to be taken once a day, areparticularly preferred.

Also preferred are pharmaceutical compositions containing at least 0.05to 90.0% of the active ingredient, in particular low effective doses, inorder to prevent side effects or analgesic effects. Conventionally, 0.1to 5000 mg of the combination per kg of body weight, in particular 1 to500 mg per kg, preferably 2 to 250 mg per kg are administered. Alsopreferred and conventional, however, is the administration of 0.01 to 5mg/kg, preferably 0.03 to 2 mg/kg, in particular 0.05 to 1 mg/kg of bodyweight.

Examples of suitable auxiliaries may include: water, ethanol,2-propanol, glycerol, ethylene glycol, propylene glycol, polyethyleneglycol, polypropylene glycol, glucose, fructose, lactose, saccharose,dextrose, molasses, starch, modified starch, gelatine, sorbitol,inositol, mannitol, microcrystalline cellulose, methyl cellulose,carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol,polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums,acacia gum, alginates, dextran, saturated and unsaturated fatty acids,stearic acid, magnesium stearate, zinc stearate, glycerol stearate,sodium lauryl sulphate, edible oils, sesame oil, coconut oil, peanutoil, soybean oil, lecithin, sodium lactate, polyoxyethylene andpolypropylene fatty acid ester, sorbitan fatty acid ester, sorbic acid,benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride,potassium chloride, magnesium chloride, calcium chloride, magnesiumoxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide,magnesium sulphate, zinc sulphate, calcium sulphate, potash, calciumphosphate, dicalcium phosphate, potassium bromide, potassium iodide,talcum, kaolin, pectin, Crospovidon, agar and bentonite.

The pharmaceutical compositions according to the invention are producedusing means, devices, methods and processes that are well known in theprior art of pharmaceutical formulations, as described for example in“Remington's Pharmaceutical Sciences”, A.R. Gennaro (ed.), 17^(th)edition, Mack Publishing Company, Easton, Pa. (1985), in particular inpart 8, chapters 76 to 93.

Thus, for a solid formulation, such as a tablet, for example, the activeingredient of the pharmaceutical composition may be granulated with apharmaceutical carrier, for example conventional tablet ingredients suchas corn starch, lactose, saccharose, sorbitol, talcum, magnesiumstearate, dicalcium phosphate or pharmaceutically acceptable gums, andpharmaceutical diluents, for example water, in order to form a solidcomposition that contains an active ingredient in homogeneousdistribution. The term “homogeneous distribution” is taken to mean thatthe active ingredient is distributed uniformly over the entirecomposition, so that said composition may easily be divided into equallyeffective unit dose forms, such as tablets, pills or capsules. The solidcomposition is then divided into unit dose forms. The tablets or pillsof the pharmaceutical composition according to the invention or of thecompositions according to the invention may also be coated or compoundedin a different manner, in order to provide a dose form with a delayedrelease. Suitable coating agents include polymer acids and mixtures ofpolymer acids with materials such as shellac, cetyl alcohol and/orcellulose acetate.

The invention also relates to a method for the treatment of pain inwhich the active ingredient according to the invention is used.

A further preferred subject of the invention is a therapy, in particulara therapy regimen, in which, in order to treat pain, a COX-II inhibitoris given before giving the analgesic3-(3-dimethylamino-1-ethyl-2-methyl-proply)-phenol compound, as this hasproven to be particularly advantageous. Particularly preferably, theCOX-II inhibitor is given at least 30 minutes, preferably 1 hour beforegiving the 3-(3-dimethylamino-1-ethyl-2-methyl-proply)-phenol compound.This may be done, for example, directly by the relevant doctor, but also(for example, on the doctor's instructions) by the patient himself. Theactive ingredient combination may also be separated into variouspharmaceutical preparations, and may in particular also be in the formof various pharmaceutical packages. A possible and also advantageousembodiment of this invention would be a kit in which the activeingredients of the active ingredient combination according to theinvention, although spatially separated, are provided in a presentationform, for example a pharmaceutical composition package. A “kit” of thistype is accordingly also a preferred embodiment of the invention.

EXAMPLES

The following examples are intended to illustrate and clarify certainembodiments of the invention, however they are not intended to andshould not be understood to limit the subject matter of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are bar graphs showing the effect of two different dosagesof (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol in theRandall-Selitto test, as well as the effects of individualadministrations of the COX-II inhibitors, the expected additive effectsof administrations of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and theCOX-II inhibitors, and the surprising supra-additive effects achieved bythe combination of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and theCOX-II inhibitors in the Randall-Selitto test described below, in thecase of staggered administration. The COX inhibitors (compound 104 or103) were administered perorally to rats 1 hour before theadministration of the(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol compound.

AUD=area under data.% MPE=% of the maximum possible effect, wherein the maximum possibleeffect=100%.

EXAMPLE 1 Effects in the Randall-Selitto Test

The compounds, which were tested with regard to their efficacy, arelisted below. The numbering is used in the examples and the figures:

Test Compound: (compound no. 2)(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,hydrochloride

COX II-Inhibitors:

Name Compound No. Celecoxib 101 Rofecoxib 102 Celecoxib in the form ofthe final pharmaceutical 103 composition CELEBREX ® Rofecoxib in theform of the final pharmaceutical 104 composition VIOXX ®

EXAMPLE 2 Writhing Test on Mouse

The writhing test is a modification of the method of Schmauss C andYaksh TL, J Pharmacol Exp Ther 228: 1-12 (1984) and a model for acutepain.

9% acetic acid was administered to the animals intraperitoneally as apain stimulus. This was administered 30 min (test substance perorally)or 10 min (test substance intravenously) after the administration of thetest substance. The pain-induced writhing reactions were recorded 10 to35 min after the administration of acetic acid. As rats rarely exhibitthe conventional writhing reaction of mice, but do exhibit other veryclear expressions of pain, the evaluation took place on the basis of ascore division. Pain expressions, such as a slanting body angle when theanimal stands upright, frequent cleaning of the belly or arching of theback without stretching of the rear limbs, were thus included in theevaluation.

The animals that had been treated with the substance were compared witha control group, which had been given physiological saline solution. Thegroup contained 10 animals (n=10).

The result of the administration of compound no 2 as well as the resultof administrations of the active ingredient combination of compound no.2 with the COX-II inhibitors 101, 102, 103 and 104 can be seen fromTable 1.

EXAMPLE 3 Formalin Test

The formalin test (Dubuisson, D. and Dennis, S.G., 1977, Pain, 4, 161 to174) is a model for acute and chronic pain. In the tests presented here,the chronic pain component was evaluated.

By means of a single formalin injection into the dorsal side of a hindpaw of test animals that were able to move freely, a biphasicnociceptive reaction, which was detected by the observation of threeclearly distinguishable behavioral patterns, was induced.

Formalin having a volume of 20 μl and a concentration of 1% wasadministered subcutaneously into the dorsal side of the right hind pawof each animal. The specific behavioural changes, such as raising andshaking of the paw, weight loss in the animal and biting and lickingreactions, were continuously observed and registered for up to 60 minafter the formalin administration. The behavioral changes were weighteddifferently (a score of 0 to 3) and a pain rate (PR) calculated havingthe general formula:

PR=[(T₀×0)+(T₁×1)+(T₂×2)+(T₃×3)/180.

T₀, T₁, T₂ and T₃ each correspond to the time in seconds during whichthe animal exhibited behavioural pattern 0, 1, 2 or 3. The groupcontained 10 animals (n=10).

The result of the administration of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolhydrochloride, as well as the result of administrations of combinationsof compound no. 2 with the COX-II inhibitors 101, 102, 103 and 104 canbe seen from Table 1.

EXAMPLE 4 Randell-Selitto Test

The Randell-Selitto test of Randall and Selitto (Arch. Int.Pharmacodyn., 1957, 111: 409 to 419) is a model for inflammatory pain.

By means of the injection of 0.1 ml 20% baking yeast suspensionventrally into a hind paw an oedema was induced, on which pain wasgenerated 4 hours later by continuously increasing pressure with a stamp(2 mm tip diameter). The measured value to be determined and at the sametime also the end point of the pain test was the pressure at which thevocalisation reaction of the animal occurred. The percentage maximumpossible effect (% MPE) was calculated. The maximum pressure of thestamp was 250 g. The group size was n=10.

The results of administration of(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,hydrochloride as well as the results of administrations of combinationsof compound no. 2 with COX-II inhibitors can be seen from FIGS. 1 to 2and the following Table 1.

EVALUATION

The selected analgesic,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl phenol (compound 2),exhibited a moderately strong to strong inhibition of nociception orhyperalgesia in the animal test models.

The theoretical additive value was calculated by adding the mean valuesfrom the individual tests of the test substance and COX-II inhibitor.The corresponding standard deviation of the theoretical additive meanvalue was calculated from the addition of the variances.

In all of the above-listed animal models, the selected3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol analgesic compoundexhibited a moderately strong to strong inhibition of nociception orhyperalgesia. (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenolshowed, in particular, good efficacy in the Randall-Sellito testindicative of usefulness to treat inflammatory pain.

The simultaneous administration of a selective COX-II inhibitor(Rofecoxib or Celecoxib) with compound 2 in the Randall-Selitto test forinflammatory pain resulted in an intensification of effect in comparisonto the theoretically calculated purely additive effect. A cleareffect-increasing supra-additive effect in the Randall-Selitto test isto be highlighted in the case of the staggered administration of COX-IIinhibitor and the selected analgesic(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (compound 2).In these tests, either Rofecoxib or Celecoxib was administered 1 hourprior to the administration of the(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol. In a fewtests, Rofecoxib was administered as the final preparation Vioxx andCelecoxib as Celebrex.

Results of the tests are summarized in the following table (Table 1).Fixed ratio combination: equieffective dose of the two substances,calculated from the ratio of the respective ED50 values. Fixed dosecombination: fixed doses of the respective substances.

TABLE 1 Dose of % effect/ED50 Ratio of compound A (1) [mg/kg] of %effect/ED50 Compound No./ compound A (1) and COX-II % effect/ED50combination [mg/kg] of Test combination Method of to COX-II inhibitor(2) % effect/ED50 [mg/kg] of (theoretical combination (animal (compoundadministra- inhibitor (2) [mg/kg] [mg/kg] of COX-II additive(experimental model) A + COX II) tion 1: 2: 1: 2: compound A inhibitorvalue) value) Fixed ratio combination Writhing 2 + 102 peroral 1 2 — —ED₅₀: 33.0 ED₅₀: 60.1 ED₅₀: 47.0 ED₅₀: 23.3 (rat) Formalin 2 + 101peroral 47.3 52.7 — — ED₅₀: 34.6 ED₅₀: 38.5 ED₅₀: 36.5 ED₅₀: 22.8 test(mouse) Formalin 2 + 101 peroral 10.5 89.5 — — ED₅₀: 18.0 ED₅₀: 154ED₅₀: 86.0 ED₅₀: 60.6 test (rat) Fixed dose combination: Randall- 2 +104 peroral — — 31 215 13.3 11.2 24.5 29.7 Selitto (rat) Randall- 2 +101 peroral — — 31 215 13.3 9.8 23.1 29.6 Selitto (rat) Fixed dosecombination (staggered administration; COX inhibitor 1 hour prior tocompound A): Randall- 2 + 104 peroral — — 31 215 20.0 13.0 33.0 45.7Selitto (rat) Randall- 2 + 104 peroral — — 46 215 32.6 13.0 45.6 59.8Selitto (rat) Randall- 2 + 103 peroral — — 31 215 20.0 17.3 37.3 60.9Selitto (rat) Randall- 2 + 103 peroral — — 46 215 32.6 17.3 49.9 86.1Selitto (rat)

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations fallingwithin the scope of the appended claims and equivalents thereof.

1. A method of treating or inhibiting pain due to inflammation in apatient in need thereof, said method comprising administering to saidpatient an effective inflammatory pain alleviating amount of a(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol compound.
 2. Amethod according to claim 1, wherein the compound is present in the formof a physiologically acceptable salt.
 3. A method according to claim 2,wherein the physiologically acceptable salt is a hydrochloride salt. 4.A method according to claim 2, wherein the physiologically acceptablesalt is a citrate salt.
 5. A method according to claim 1, wherein thecompound is present in free base form.
 6. A method according to claim 1,wherein the compound is present in the form of a pure enantiomer or purediastereoisomer.
 7. A method according to claim 1, wherein said patientis a mammal.